CN102746324A - Purification method of cefotiam hydrochloride and aseptic powder injection of cefotiam hydrochloride - Google Patents
Purification method of cefotiam hydrochloride and aseptic powder injection of cefotiam hydrochloride Download PDFInfo
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- CN102746324A CN102746324A CN2012102641684A CN201210264168A CN102746324A CN 102746324 A CN102746324 A CN 102746324A CN 2012102641684 A CN2012102641684 A CN 2012102641684A CN 201210264168 A CN201210264168 A CN 201210264168A CN 102746324 A CN102746324 A CN 102746324A
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- cefotiam
- cefotiam hydrochloride
- hydrochloride
- purification process
- bullion
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- 229960004700 cefotiam hydrochloride Drugs 0.000 title claims abstract description 105
- 239000000843 powder Substances 0.000 title claims abstract description 64
- 238000002347 injection Methods 0.000 title claims abstract description 35
- 239000007924 injection Substances 0.000 title claims abstract description 35
- 238000000746 purification Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title abstract description 12
- BWRRTAXZCKVRON-DGPOFWGLSA-N cefotiam dihydrochloride Chemical compound Cl.Cl.CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 BWRRTAXZCKVRON-DGPOFWGLSA-N 0.000 title abstract 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical class N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000005406 washing Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 7
- SVSFIELZISOJDT-XRZFDKQNSA-N (6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-3-[[1-[2-(dimethylamino)ethyl]tetrazol-5-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrochloride Chemical compound Cl.CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 SVSFIELZISOJDT-XRZFDKQNSA-N 0.000 claims description 101
- 238000000967 suction filtration Methods 0.000 claims description 23
- 238000010521 absorption reaction Methods 0.000 claims description 20
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 18
- 239000012535 impurity Substances 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 238000007710 freezing Methods 0.000 claims description 4
- 230000008014 freezing Effects 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000003610 charcoal Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 2
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 abstract description 46
- 229960001242 cefotiam Drugs 0.000 abstract description 46
- 239000013078 crystal Substances 0.000 abstract description 33
- 238000001914 filtration Methods 0.000 abstract description 29
- 239000003814 drug Substances 0.000 abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 2
- 239000012043 crude product Substances 0.000 abstract 1
- 239000002510 pyrogen Substances 0.000 abstract 1
- OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- 238000001228 spectrum Methods 0.000 description 23
- 230000014759 maintenance of location Effects 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000012856 packing Methods 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 150000002829 nitrogen Chemical class 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000002932 luster Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- 0 CCCN(C)C(C)SCC(CS[C@]1[C@]2(C)NC(CC3*C(*)SC3)=O)=C(C(O)=O)N1C2=O Chemical compound CCCN(C)C(C)SCC(CS[C@]1[C@]2(C)NC(CC3*C(*)SC3)=O)=C(C(O)=O)N1C2=O 0.000 description 1
- JFPVXVDWJQMJEE-QMTHXVAHSA-N Cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)C(=NOC)C1=CC=CO1 JFPVXVDWJQMJEE-QMTHXVAHSA-N 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- UISNQGBURSTLKO-UHFFFAOYSA-N Cl.Cl.CC(=CCCCCC)C(=O)O Chemical class Cl.Cl.CC(=CCCCCC)C(=O)O UISNQGBURSTLKO-UHFFFAOYSA-N 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
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- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
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- 206010006451 bronchitis Diseases 0.000 description 1
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- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
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- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Images
Abstract
The invention relates to the technical field of medicaments, and particularly relates to a purification method of cefotiam hydrochloride and an aseptic powder injection of cefotiam hydrochloride. The method comprises the steps of: dissolving cefotiam sodium hydrochloride crude product with water, adding activated carbon for injection to remove pyrogen, then adding acetone, recrystallizing, washing obtained crystal with ethyl ether or methyl tert-butyl ether, filtering, carrying out suction filtering water-saturated nitrogen gas, drying under reduced-pressure to obtain cefotiam aseptic powder which is low in organic residue, pyrogen-free and high in purity.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, particularly a kind of purification process of cefotiam hydrochloride and cefotiam hydrochloride sterile powder injection.
Background technology
Cefotiam hydrochloride; English name is Cefotiam Hydrochoride; Its chemical name is ((6R; 7R) [2-(2-amino-1,3-thiazoles-4-yl) acetamido]-3 [[1-(2-dimethylaminoethyl)-1H-tetrazolium-5-yl] thiomethyl]-8-oxygen-5-sulphur-1-nitrogen two ring [4.2.0] oct-2-ene-2-carboxylic acid dihydrochlorides).Structural formula is suc as formula shown in the I:
The formula I
Cefotiam is by the research and development of Japanese Wu Tian company, and 1981 first at the semi-synthetic cynnematin of the s-generation of Japan's listing.These article are approaching to the effect and the Kefzol (cefazolin) of gram positive organism; To gram-negative bacteria; More excellent like effects such as influenzae, escherichia coli, klebsiella spp, Proteus mirabilises, enterobacteria, citrobacter, the positive Bacillus proteus of indoles etc. also there are anti-microbial effect.The quiet notes administration of the dihydrochloride of clinical use is mainly used in the infection of treatment due to the sensitive organism, like infection due to pneumonia, bronchitis, biliary tract infection, peritonitis, urinary tract infections and operation and the wound and septicemia etc.
Because cefotiam hydrochloride is positioned in the storage process, particularly 50 ℃ of high temperature (>) condition under, degraded often takes place react with polymerization, thereby cause the reduction of active constituents of medicine content, color and luster reinforcement, the rising of polymeric impurities content.In addition, cross the cefotiam hydrochloride of validity period, because the shelf-time is long, active constituents of medicine content is reduced, darken, polymer content is high especially, and polymer content is prone to make human body to produce anaphylaxis when high.In order to ensure the human body drug safety; National Specification, cefotiam hydrochloride requires the single impurity peak area of cefotiam must not surpass 1% of main peak area; Each impurity peak area with must not surpass 3% of main peak area; The content of polymkeric substance is not higher than 0.5%, and the content of cefotiam is not less than 83.2%, and its color and luster is not higher than look No. 6.And in processes such as depositing of cefotiam; The major impurity that the cefotiam degraded produces is the verivate of 1-(2-dimethyl aminoethyl)-1H-5-sulfydryl-tetrazole (structure is suc as formula shown in the III) and cephalo parent nucleus (7-ACA); The verivate of cephalo parent nucleus (7-ACA) mainly comprises: 7-ACA (structure is suc as formula shown in the II), 7-ACA-HACA (structure is suc as formula shown in the IV), 7-DMT (structure is suc as formula shown in the V), 7-ATA lactone (structure is suc as formula shown in the VI) etc.; And this also is the synthesis material or the synthesising by-product of cefotiam hydrochloride, and is residual easily in cefotiam hydrochloride.So or cefotiam or its salt that foreign matter content high residual for this type impurity are necessary to be further purified, and obtain the high cefotiam hydrochloride crystal of purity.
Formula II formula III
The formula IV
Formula V formula VI
The purification process of the cefotiam hydrochloride of report mainly is a method of utilizing water-acetone recrystallization at present, but the cefotiam hydrochloride that utilizes this method to process causes the acetone solvent in the bulk drug to exceed standard easily.The residual quantity of acetone must not surpass 0.5% limit when being defined in the finished product exsiccant in technical director's principle of the chemicals residual solvent research of issuing according to State Food and Drug Administration; And the problem that the cefotiam hydrochloride that the crystal that utilizes water-acetone recrystallization to obtain obtains through vacuum-drying all exists acetone to exceed standard; And the content of acetone generally in the 1.5-3.7% scope, seriously exceeds the limit of pharmacopeia regulation.
Therefore, provide a kind of purification process of cefotiam hydrochloride and cefotiam hydrochloride sterile powder injection to have realistic meaning.
Summary of the invention
In view of this, the present invention provides a kind of purification process and cefotiam hydrochloride sterile powder injection of cefotiam hydrochloride.This method water dissolution hydrochloric acid cefotiam sodium bullion adds the injection gac and removes thermal source; Add acetone then and carry out recrystallization; The gained crystal is after ether or MTBE are washed and starched; Filter again through the saturated nitrogen suction filtration of water flowing, obtain low organic residual, pyrogen-free, cefotiam aseptic powder that purity is high behind the drying under reduced pressure.
In order to realize the foregoing invention purpose, the present invention provides following technical scheme:
The invention provides a kind of purification process of cefotiam hydrochloride, may further comprise the steps:
Step 1: obtain the cefotiam hydrochloride bullion, it mainly contains the verivate of impurity 1-(2-dimethyl aminoethyl)-1H-5-sulfydryl-tetrazole (structure is suc as formula shown in the III) and/or cephalo parent nucleus.
Step 2: after getting the cefotiam hydrochloride bullion and being dissolved in water, heating, add charcoal absorption, filter through first and collect first filtrating, add after acetone mixes, filter through second and collect second filtrating, freezing crystallization is collected solid;
Step 3: after getting the washing of solid adding ether solvent, first suction filtration, feed water saturation nitrogen through second suction filtration, dry, pulverizing promptly gets.
As preferably, the verivate of the cephalo parent nucleus in the step 1 in the cefotiam hydrochloride bullion impurity is mainly the verivate of 7-ACA.
Preferably, in the step 1 in the cefotiam hydrochloride bullion impurity verivate of 7-ACA be a kind of in 7-ACA (structure is suc as formula shown in the II), 7-ACA-HACA (structure is suc as formula shown in the IV), 7-DMT (structure is suc as formula shown in the V), the 7-ATA lactone or mixtures that both are above.
As preferably, the temperature of heating is 50～60 ℃ in the step 1.
As preferably, in g/mL, the mass volume ratio of cefotiam hydrochloride bullion and acetone is 1:0.5～6 in the step 2.
As preferably, ether solvent is ether or MTBE in the step 3.
As preferably, in g/mL, the mass volume ratio of cefotiam hydrochloride bullion and ether solvent is 1:0.25～6 in the step 3.
As preferably, the time of second suction filtration is 3～6h in the step 3.
As preferably, in g/mL, the mass volume ratio of cefotiam hydrochloride bullion and water is 1:0.5～2 in the step 2.
Preferably, in g/mL, the mass volume ratio of cefotiam hydrochloride bullion and water is 1:0.5～1 in the step 2.
As preferably, the mass ratio of cefotiam hydrochloride bullion and gac is 100:0.05～1 in the step 2.
Preferably, the mass ratio of cefotiam hydrochloride bullion and gac is 100:0.1～0.6 in the step 2.
As preferably, add charcoal absorption in the step 2 and be specially with gac reflux 30min.
As preferably, second is filtered into below 0.1Mpa in the step 2, with 0.22 μ m filtering with microporous membrane.
As preferably, the temperature of freezing crystallization is-5～5 ℃ in the step 2.
As preferably, drying is specially at 20～40 ℃ of following drying under reduced pressure in the step 3.
The present invention also provides a kind of cefotiam hydrochloride sterile powder injection, and it is made up of cefotiam hydrochloride and acceptable accessories that above-mentioned purification process obtains.
As preferably, acceptable accessories is a soda ash light.
Purification process provided by the invention adopts water dissolution hydrochloric acid cefotiam sodium bullion to add the injection gac and removes thermal source; Add acetone then and carry out recrystallization; The gained crystal is after ether or MTBE are washed and starched; Filter again through the saturated nitrogen suction filtration of water flowing, obtain low organic residual, pyrogen-free, cefotiam aseptic powder that purity is high behind the drying under reduced pressure.Preparing method according to the invention utilizes ether or MTBE to wash and starch; Part acetone in can the flush away cefotiam hydrochloride; Through the saturated nitrogen suction filtration of water flowing, can effectively replace the solvent that wraps up in the cefotiam again, effectively solve the problem that acetone exceeds standard in the cefotiam hydrochloride; And through detecting, the residual quantity of acetone in the cefotiam hydrochloride and ether or MTBE all meets the pharmacopeia requirement.And because the boiling point of ether is lower, in big production, cause danger easily, therefore in the preparation process, be preferably MTBE.In addition, it is higher to adopt preparation method according to the invention to prepare the yield of cefotiam hydrochloride aseptic powder, reaches 80～90%, and can effectively remove the related substance in the cefotiam hydrochloride.
Description of drawings
Fig. 1 shows the HPLC color atlas of the cefotiam bullion in the embodiment of the invention 1～3; Wherein relative retention time is that the peak of 21.424min is the absorption peak of cefotiam; The peak of all the other relative retention times is impurity peaks, and wherein the peak of 3.249min is the absorption peak of 7-ACA, and the peak of 3.778min is the absorption peak of 1-(2-dimethyl aminoethyl)-1H-5-sulfydryl-tetrazole; 4.428min the peak be the absorption peak of 7-ATA-HACA, the absorption peak of the peak 7-DMT of 5.995min;
Fig. 2 shows the HPLC color atlas of the cefotiam aseptic powder that the embodiment of the invention 1 makes, and wherein relative retention time is that the peak of 21.245min is the absorption peak of cefotiam, and the peak of all the other relative retention times is impurity peaks;
Fig. 3 shows the HPLC color atlas of the cefotiam aseptic powder that the embodiment of the invention 2 makes, and wherein relative retention time is that the peak of 21.624min is the absorption peak of cefotiam, and the peak of all the other relative retention times is impurity peaks;
Fig. 4 shows the HPLC color atlas of the cefotiam aseptic powder that the embodiment of the invention 3 makes, and wherein relative retention time is that the peak of 21.437min is the absorption peak of cefotiam, and the peak of all the other relative retention times is impurity peaks;
Fig. 5 shows the HPLC color atlas of the cefotiam bullion in the embodiment of the invention 4～7; Wherein relative retention time is that the peak of 19.597min is the absorption peak of cefotiam; The peak of all the other relative retention times is impurity peaks, and wherein the peak of 3.499min is the absorption peak of 1-(2-dimethyl aminoethyl)-1H-5-sulfydryl-tetrazole, and the peak of 3.982min is the absorption peak of 7-ATA-HACA; 5.428min the peak be the absorption peak of 7-DMT, the peak of 18.407min is the absorption peak of 7-ATA lactone;
Fig. 6 shows the HPLC color atlas of the cefotiam aseptic powder that the embodiment of the invention 4 makes, and wherein relative retention time is that the peak of 21.320min is the absorption peak of cefotiam, and the peak of all the other relative retention times is impurity peaks;
Fig. 7 shows the HPLC color atlas of the cefotiam aseptic powder that the embodiment of the invention 5 makes, and wherein relative retention time is that the peak of 19.887min is the absorption peak of cefotiam, and the peak of all the other relative retention times is impurity peaks;
Fig. 8 shows the HPLC color atlas of the cefotiam aseptic powder that the embodiment of the invention 6 makes, and wherein relative retention time is that the peak of 21.245min is the absorption peak of cefotiam, and the peak of all the other relative retention times is impurity peaks;
Fig. 9 shows the HPLC color atlas of the cefotiam aseptic powder that the embodiment of the invention 7 makes, and wherein relative retention time is that the peak of 20.083min is the absorption peak of cefotiam, and the peak of all the other relative retention times is impurity peaks.
Embodiment
The invention discloses a kind of purification process and cefotiam hydrochloride sterile powder injection of cefotiam hydrochloride, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as and are included in the present invention.Method of the present invention and application are described through preferred embodiment; The related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use technology of the present invention.
Agents useful for same all can be buied by market in the purification process of a kind of cefotiam hydrochloride provided by the invention and the cefotiam hydrochloride sterile powder injection.
Below in conjunction with embodiment, further set forth the present invention:
The purifying of embodiment 1 cefotiam hydrochloride bullion, the preparation of cefotiam hydrochloride sterile powder injection
Taking by weighing purity is that 92.1% cefotiam hydrochloride bullion (wherein impure 7-ACA, DMMT, 7-ATA-HACA, 7-DMT) 500g adds in the reaction kettle, after the water dissolution of adding 1L, adds the 2.0g injection and uses gac, is heated to 50 ℃, the 30min after-filtration; Get gained filtrating after the filtration, add 3L acetone, the heated and stirred dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration; Filtrating is refrigerated to 0 ℃, and low temperature crystallization 2 hours, after crystallization is accomplished, filter; The gained crystal is put into crystallizer, the MTBE that the adds 1.5L washing of pulling an oar, suction filtration must white crystal; In white crystal, feed water saturation nitrogen again, behind the suction filtration 4h, 25 ℃ of vacuum-dryings 6 hours; Crystal is pulverized, got white hydrochloride cefotiam aseptic powder 423.5g, yield is 84.7%, and purity is 99.0%, and the acetone residual quantity is 0.124%, and the MTBE residual quantity is 0.167%.。
Cefotiam hydrochloride aseptic powder and soda ash light are mixed the back packing, get the cefotiam hydrochloridefor inj sterile powder injection.
Wherein, the HPLC spectrum data of cefotiam hydrochloride bullion is seen table 1, and the HPLC spectrum data that makes the cefotiam hydrochloride aseptic powder after purified is seen table 2.
The HPLC spectrum data of table 1 cefotiam hydrochloride bullion
| Peak number | RT | The area percentage composition |
| 1 | 2.849 | 0.3786 |
| 2 | 3.249 | 4.5691 |
| 3 | 3.778 | 0.1335 |
| 4 | 4.207 | 0.1814 |
| 5 | 4.428 | 0.4428 |
| 6 | 5.032 | 0.0312 |
| 7 | 5.449 | 0.2307 |
| 8 | 5.995 | 1.2009 |
| 9 | 7.478 | 0.0428 |
| 10 | 8.791 | 0.0163 |
| 11 | 10.899 | 0.0488 |
| 12 | 12.187 | 0.0488 |
| 13 | 15.624 | 0.2863 |
| 14 | 17.445 | 0.2828 |
| 15 | 21.424 | 92.1062 |
| Add up to | —— | 100.0000 |
The HPLC spectrum data of table 2 cefotiam hydrochloride aseptic powder
| Peak number | RT | The area percentage composition |
| 1 | 3.253 | 0.4700 |
| 2 | 3.849 | 0.1125 |
| 3 | 4.428 | 0.0389 |
| 4 | 5.099 | 0.0713 |
| 5 | 6.037 | 0.0705 |
| 6 | 7.470 | 0.0688 |
| 7 | 11.012 | 0.0537 |
| 8 | 17.887 | 0.1122 |
| 9 | 21.245 | 99.0021 |
| Add up to | —— | 100.0000 |
The purifying of embodiment 2 cefotiam hydrochloride bullions, the preparation of cefotiam hydrochloride sterile powder injection
Taking by weighing purity is that 92.1% cefotiam hydrochloride bullion (wherein impure 7-ACA, DMMT, 7-ATA-HACA, 7-DMT) 500g adds in the reaction kettle, after the water dissolution of adding 0.5L, adds the 3.0g injection and uses gac, is heated to 60 ℃, the 30min after-filtration; Get gained filtrating, add 2L acetone, the heated and stirred dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration; Filtrating is refrigerated to 0 ℃, and low temperature crystallization 2 hours, after crystallization is accomplished, filter; The gained crystal is put into crystallizer, the ether that the adds 2L washing of pulling an oar, suction filtration must white crystal; In white crystal, feed water saturation nitrogen again, behind the suction filtration 5h, 25 ℃ of vacuum-dryings 3 hours; Crystal is pulverized, got white hydrochloride cefotiam aseptic powder 436.5g, yield is 87.3%, and purity is 99.2%, and the acetone residual quantity is 0.206%, and the ether residual quantity is 0.165%.
Cefotiam hydrochloride aseptic powder and soda ash light are mixed the back packing, get the cefotiam hydrochloridefor inj sterile powder injection.
Wherein, the HPLC spectrum data of cefotiam hydrochloride bullion is seen table 1, and the HPLC spectrum data that makes the cefotiam hydrochloride aseptic powder after purified is seen table 3.
The HPLC spectrum data of table 3 cefotiam hydrochloride aseptic powder
| Peak number | RT | The area percentage composition |
| 1 | 3.257 | 0.2926 |
| 2 | 3.857 | 0.0848 |
| 3 | 5.153 | 0.0722 |
| 4 | 6.082 | 0.0415 |
| 5 | 7.541 | 0.0386 |
| 6 | 11.216 | 0.0594 |
| 7 | 12.312 | 0.1361 |
| 8 | 15.441 | 0.0106 |
| 9 | 18.137 | 0.0883 |
| 10 | 21.624 | 99.1760 |
| Add up to | —— | 100.0000 |
The purifying of embodiment 3 cefotiam hydrochloride bullions, the preparation of cefotiam hydrochloride sterile powder injection
Taking by weighing purity is that 92.1% cefotiam hydrochloride bullion (wherein impure 7-ACA, DMMT, 7-ATA-HACA, 7-DMT) 500g adds in the reaction kettle, after the water dissolution of adding 0.5L, adds the 5.0g injection and uses gac, is heated to 55 ℃, the 30min after-filtration; Get gained filtrating, add 2L acetone, the heated and stirred dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration; Filtrating is refrigerated to 0 ℃, and low temperature crystallization 2 hours, after crystallization is accomplished, filter; The gained crystal is put into crystallizer, the MTBE that the adds 1.5L washing of pulling an oar, suction filtration must white crystal; In white crystal, feed water saturation nitrogen again, behind the suction filtration 4h, 25 ℃ of vacuum-dryings 4 hours; Crystal is pulverized, got white hydrochloride cefotiam aseptic powder 441.5g, yield is 88.3%, and purity is 99.0%, and the acetone residual quantity is 0.246%, and the MTBE residual quantity is 0.167%.
Cefotiam hydrochloride aseptic powder and soda ash light are mixed the back packing, get the cefotiam hydrochloridefor inj sterile powder injection.
Wherein, the HPLC spectrum data of cefotiam hydrochloride bullion is seen table 1, and the HPLC spectrum data that makes the cefotiam hydrochloride aseptic powder after purified is seen table 4.
The HPLC spectrum data of table 4 cefotiam hydrochloride aseptic powder
| Peak number | RT | The area percentage composition |
| 1 | 3.257 | 0.3842 |
| 2 | 3.870 | 0.1143 |
| 3 | 4.433 | 0.0243 |
| 4 | 5.153 | 0.0747 |
| 5 | 6.087 | 0.0747 |
| 6 | 7.495 | 0.0627 |
| 7 | 11.241 | 0.0541 |
| 8 | 12.233 | 0.0813 |
| 9 | 18.287 | 0.1219 |
| 10 | 21.437 | 99.0078 |
| Add up to | —— | 100.0000 |
The purifying of embodiment 4 cefotiam hydrochloride bullions, the preparation of cefotiam hydrochloride sterile powder injection
Taking by weighing purity is that 86.2% cefotiam hydrochloride bullion (wherein impure DMMT, 7-DMT, 7-ATA lactone) 500g adds in the reaction kettle, after the water dissolution of adding 0.25L, adds the 5.0g injection and uses gac, is heated to 52 ℃, the 30min after-filtration; Get gained filtrating after the filtration, add 0.25L acetone, the heated and stirred dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration; Filtrating is refrigerated to-5 ℃, and low temperature crystallization 2 hours, after crystallization is accomplished, filter; The gained crystal is put into crystallizer, the ether that the adds 0.125L washing of pulling an oar, suction filtration must white crystal; In white crystal, feed water saturation nitrogen again, behind the suction filtration 3h, 40 ℃ of vacuum-dryings 6 hours; Crystal is pulverized, got white hydrochloride cefotiam aseptic powder 430.5g, yield is 86.1%, and purity is 95.8%, and the acetone residual quantity is 0.305%, and the ether residual quantity is 0.104%.
Cefotiam hydrochloride aseptic powder and soda ash light are mixed the back packing, get the cefotiam hydrochloridefor inj sterile powder injection.
Wherein, the HPLC spectrum data of cefotiam hydrochloride bullion is seen table 5, and the HPLC spectrum data that makes the cefotiam hydrochloride aseptic powder after purified is seen table 6.
The HPLC spectrum data of table 5 cefotiam hydrochloride bullion
| Peak number | RT | The area percentage composition |
| 1 | 3.499 | 7.7636 |
| 2 | 3.982 | 0.0311 |
| 3 | 4.956 | 1.7958 |
| 4 | 5.428 | 0.4521 |
| 5 | 6.128 | 0.0216 |
| 6 | 6.495 | 0.6153 |
| 7 | 7.570 | 0.9731 |
| 8 | 8.570 | 0.0423 |
| 9 | 9.041 | 0.1101 |
| 10 | 10.720 | 0.0164 |
| 11 | 11.649 | 0.6973 |
| 12 | 16.528 | 0.1913 |
| 13 | 18.407 | 0.6868 |
| 14 | 19.591 | 86.1538 |
| 15 | 24.937 | 0.4492 |
| Add up to | —— | 100.0000 |
The HPLC spectrum data of table 6 cefotiam hydrochloride aseptic powder
| Peak number | RT | The area percentage composition |
| 1 | 2.928 | 0.1487 |
| 2 | 3.253 | 1.6599 |
| 3 | 3.849 | 0.2418 |
| 4 | 4.449 | 0.1078 |
| 5 | 5.128 | 0.0701 |
| 6 | 5.670 | 0.0371 |
| 7 | 6.053 | 0.0683 |
| 8 | 7.470 | 0.0369 |
| 9 | 8.307 | 0.0724 |
| 10 | 8.953 | 0.0581 |
| 11 | 11.124 | 0.0511 |
| 12 | 12.137 | 0.1124 |
| 13 | 13.366 | 0.0360 |
| 14 | 18.108 | 0.7502 |
| 15 | 19.820 | 0.3006 |
| 16 | 21.320 | 95.7617 |
| 17 | 26.528 | 0.2145 |
| 18 | 28.795 | 0.2725 |
| Add up to | —— | 100.0000 |
The purifying of embodiment 5 cefotiam hydrochloride bullions, the preparation of cefotiam hydrochloride sterile powder injection
Taking by weighing purity is that 86.2% cefotiam hydrochloride bullion (wherein impure DMMT, 7-DMT, 7-ATA lactone) 500g adds in the reaction kettle, after the water dissolution of adding 0.5L, adds the 3.0g injection and uses gac, is heated to 58 ℃, the 30min after-filtration; Get gained filtrating after the filtration, add 1L acetone, the heated and stirred dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration; Filtrating is refrigerated to 5 ℃, and low temperature crystallization 2 hours, after crystallization is accomplished, filter; The gained crystal is put into crystallizer, the ether that the adds 3L washing of pulling an oar, suction filtration must white crystal; In white crystal, feed water saturation nitrogen again, behind the suction filtration 6h, 20 ℃ of vacuum-dryings 6 hours; Crystal is pulverized, got white hydrochloride cefotiam aseptic powder 429.5g, yield is 85.9%, and purity is 97.2%, and the acetone residual quantity is 0.402%, and the ether residual quantity is 0.356%.
Cefotiam hydrochloride aseptic powder and soda ash light are mixed the back packing, get the cefotiam hydrochloridefor inj sterile powder injection.
Wherein, the HPLC spectrum data of cefotiam hydrochloride bullion is seen table 5, and the HPLC spectrum data that makes the cefotiam hydrochloride aseptic powder after purified is seen table 7.
The HPLC spectrum data of table 7 cefotiam hydrochloride aseptic powder
| Peak number | RT | The area percentage composition |
| 1 | 3.541 | 0.9777 |
| 2 | 4.012 | 0.2099 |
| 3 | 4.712 | 0.0369 |
| 4 | 5.016 | 0.0119 |
| 5 | 5.191 | 0.0116 |
| 6 | 5.433 | 0.0244 |
| 7 | 6.120 | 0.0735 |
| 8 | 6.520 | 0.0295 |
| 9 | 7.482 | 0.0746 |
| 10 | 8.808 | 0.0327 |
| 11 | 10.466 | 0.0470 |
| 12 | 11.166 | 0.1441 |
| 13 | 12.370 | 0.0760 |
| 14 | 14.637 | 0.0942 |
| 15 | 17.670 | 0.5070 |
| 16 | 18.620 | 0.0790 |
| 17 | 19.837 | 97.1642 |
| 18 | 23.945 | 0.2399 |
| 19 | 26.470 | 0.1659 |
| Add up to | —— | 100.0000 |
The purifying of embodiment 6 cefotiam hydrochloride bullions, the preparation of cefotiam hydrochloride sterile powder injection
Taking by weighing purity is that 86.2% cefotiam hydrochloride bullion (wherein impure DMMT, 7-DMT, 7-ATA lactone) 500g adds in the reaction kettle, after the water dissolution of adding 0.75L, adds the 0.25g injection and uses gac, is heated to 57 ℃, the 30min after-filtration; Get gained filtrating after the filtration, add 2L acetone, the heated and stirred dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration; Filtrating is refrigerated to 3 ℃, and low temperature crystallization 2 hours, after crystallization is accomplished, filter; The gained crystal is put into crystallizer, the ether that the adds 1.5L washing of pulling an oar, suction filtration must white crystal; In white crystal, feed water saturation nitrogen again, behind the suction filtration 5h, 30 ℃ of vacuum-dryings 6 hours; Crystal is pulverized, got white hydrochloride cefotiam aseptic powder 421.1g, yield is 84.2%, and purity is 96.1%, and the acetone residual quantity is 0.285%, and the ether residual quantity is 0.154%.
Cefotiam hydrochloride aseptic powder and soda ash light are mixed the back packing, get the cefotiam hydrochloridefor inj sterile powder injection.
Wherein, the HPLC spectrum data of cefotiam hydrochloride bullion is seen table 5, and the HPLC spectrum data that makes the cefotiam hydrochloride aseptic powder after purified is seen table 8.
The HPLC spectrum data of table 8 cefotiam hydrochloride aseptic powder
| Peak number | RT | The area percentage composition |
| 1 | 3.249 | 1.4293 |
| 2 | 3.845 | 0.2192 |
| 3 | 4.441 | 0.0844 |
| 4 | 5.103 | 0.0695 |
| 5 | 5.645 | 0.0336 |
| 6 | 6.020 | 0.0385 |
| 7 | 7.462 | 0.0345 |
| 8 | 8.274 | 0.0735 |
| 9 | 8.891 | 0.0546 |
| 10 | 11.024 | 0.0514 |
| 11 | 12.103 | 0.2001 |
| 12 | 13.287 | 0.0781 |
| 13 | 17.945 | 0.7341 |
| 14 | 19.749 | 0.2856 |
| 15 | 21.245 | 96.1175 |
| 16 | 26.299 | 0.2281 |
| 17 | 28.695 | 0.2680 |
| Add up to | —— | 100.0000 |
The purifying of embodiment 7 cefotiam hydrochloride bullions, the preparation of cefotiam hydrochloride sterile powder injection
Taking by weighing purity is 86.2%.Cefotiam hydrochloride bullion (wherein impure DMMT, 7-DMT, 7-ATA lactone) 500g adds in the reaction kettle, after the water dissolution of adding 0.5L, adds the 0.5g injection and uses gac, is heated to 53 ℃, the 30min after-filtration; Get gained filtrating after the filtration, add 0.75L acetone, the heated and stirred dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration; Filtrating is refrigerated to 2 ℃, and low temperature crystallization 2 hours, after crystallization is accomplished, filter; The gained crystal is put into crystallizer, the MTBE that the adds 2.25L washing of pulling an oar, suction filtration must white crystal; In white crystal, feed water saturation nitrogen again, behind the suction filtration 3h, 35 ℃ of vacuum-dryings 6 hours; Crystal is pulverized, got white hydrochloride cefotiam aseptic powder 440.5g, yield is 88.1%, and purity is 97.3%, and the acetone residual quantity is 0.243%, and the MTBE residual quantity is 0.204%.
Cefotiam hydrochloride aseptic powder and soda ash light are mixed the back packing, get the cefotiam hydrochloridefor inj sterile powder injection.
Wherein, the HPLC spectrum data of cefotiam hydrochloride bullion is seen table 5, and the HPLC spectrum data that makes the cefotiam hydrochloride aseptic powder after purified is seen table 9.
The HPLC spectrum data of table 9 cefotiam hydrochloride aseptic powder
| Peak number | RT | The area percentage composition |
| 1 | 3.574 | 0.9197 |
| 2 | 4.062 | 0.1972 |
| 3 | 4.762 | 0.0313 |
| 4 | 5.070 | 0.0189 |
| 5 | 6.207 | 0.0566 |
| 6 | 6.612 | 0.0332 |
| 7 | 7.553 | 0.0721 |
| 8 | 8.962 | 0.0322 |
| 9 | 10.658 | 0.0474 |
| 10 | 11.370 | 0.1815 |
| 11 | 12.616 | 0.0888 |
| 12 | 14.841 | 0.1035 |
| 13 | 18.024 | 0.4856 |
| 14 | 18.853 | 0.0604 |
| 15 | 20.083 | 97.2907 |
| 16 | 24.403 | 0.2210 |
| 17 | 26.803 | 0.1698 |
| Add up to | —— | 100.0000 |
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (10)
1. the purification process of a cefotiam hydrochloride is characterized in that, may further comprise the steps:
Step 1: obtain the cefotiam hydrochloride bullion, the impurity in the said cefotiam hydrochloride bullion is the verivate of 1-(2-dimethyl aminoethyl)-1H-5-sulfydryl-tetrazole and/or cephalo parent nucleus;
Step 2: after getting said cefotiam hydrochloride bullion and being dissolved in water, heating, add charcoal absorption, filter through first and collect first filtrating, add after acetone mixes, filter through second and collect second filtrating, freezing crystallization is collected solid;
Step 3: after getting the washing of said solid adding ether solvent, first suction filtration, feed water saturation nitrogen through second suction filtration, dry, pulverizing promptly gets.
2. purification process according to claim 1 is characterized in that, in g/mL, the mass volume ratio of bullion of cefotiam hydrochloride described in the step 2 and acetone is 1:0.5～6.
3. purification process according to claim 1 is characterized in that, ether solvent described in the step 3 is ether or MTBE.
4. purification process according to claim 1 is characterized in that, in g/mL, the mass volume ratio of bullion of cefotiam hydrochloride described in the step 3 and said ether solvent is 1:0.25～6.
5. purification process according to claim 1 is characterized in that, the time of second suction filtration described in the step 3 is 3～6h.
6. purification process according to claim 1 is characterized in that, in g/mL, the mass volume ratio of bullion of cefotiam hydrochloride described in the step 2 and water is 1:0.5～2.
7. purification process according to claim 1 is characterized in that, the temperature of freezing crystallization described in the step 2 is-5～5 ℃.
8. purification process according to claim 1 is characterized in that, drying described in the step 3 is specially at 20～40 ℃ of following drying under reduced pressure.
9. a cefotiam hydrochloride sterile powder injection is characterized in that, it is made up of the cefotiam hydrochloride and the acceptable accessories that obtain according to each described purification process of claim 1 to 8.
10. cefotiam hydrochloride sterile powder injection according to claim 9 is characterized in that, said acceptable accessories is a soda ash light.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104337768A (en) * | 2014-08-29 | 2015-02-11 | 四川制药制剂有限公司 | Preparation method of cefotiam hydrochloride for injection |
| CN105085548A (en) * | 2015-09-10 | 2015-11-25 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical cefotiam composition for treating infectious diseases |
| CN112625052A (en) * | 2020-12-30 | 2021-04-09 | 苏州盛达药业有限公司 | Cefotiam raw material medicine |
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